Citations

The αβ T cell antigen receptor (TCR) endows T lymphocytes with immune specificity and controls their effector functions. Each person possesses a vast repertoire of TCRs that is generated by the well-studied processes of somatic recombination and thymic selection. While many antibodies specific for TCRβ variable domains are available, antibodies specific for human TCRα are rare. We now report a novel monoclonal antibody, 7F18, which binds to human TCRα constant region, with specificity for a denatured epitope that can be visualized by SDS-PAGE followed by Western blot. Both immature and mature TCR α-chain products can be visualized, making 7F18 potentially applicable to various biochemical assays of multiprotein complex assembly and maturation. This new monoclonal antibody provides a tool that can potentially facilitate the biochemical analysis of comprehensive populations of human αβ TCR complexes that need not be limited to small subsets of the repertoire.

The spinal accessory nerve (SAN) is classically considered a motor nerve innervating the sternocleidomastoid and trapezius muscles. Its anatomical relevance derives from the high prevalence of lesions following head and neck surgeries. As expected, trapezius weakness and atrophy are the most common findings; however, it is also commonly accompanied by pain and other sensory deficits that have no clear explanation, suggesting other functions. We have recently seen two patients presenting with an unrecognized sign, that is, subclavicular/pectoral asymmetry secondary to the SAN lesion. Retrospectively, we reviewed other patients with similar findings in our case series and in the literature. We discuss the anatomical connections of the SAN with the superficial cervical plexus and propose an explanation for this finding. Of the 41 patients in our series, we identified this sign in all who had preoperative photographs. New insights on the anatomy and connections of the SAN may account for the diversity of symptoms and signs presented following an operative intervention as well as the variability of its severity. Clin. Anat. 28:467–471, 2015. © 2014 Wiley Periodicals, Inc.

AbstractBackgroundSynthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM‐131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)‐1a (also called the ghrelin) receptor with approximately sixfold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin.PurposeIn this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a prespecified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders.

Objectives/HypothesisTo investigate the influence of posttreatment audiovestibular symptoms, facial neuropathy, and headache on long‐term quality‐of‐life outcomes in patients with sporadic vestibular schwannoma (VS) utilizing the Short Form 36 (SF‐36) Health Survey and the Penn Acoustic Neuroma Quality of Life (PANQOL) scale.Study DesignCross‐sectional observation study.MethodsPatients with sporadic small‐ or medium‐sized VS (< 3.0 cm) who were evaluated between 1998 and 2008 at two independent tertiary academic referral centers were surveyed. Multivariable associations with the PANQOL total score and the SF‐36 physical and mental component scores evaluated using regression analysis.ResultsA total of 538 surveyed patients returned a completed questionnaire, providing a response rate of 79%. Two hundred forty‐seven (46%) patients underwent stereotactic radiosurgery, 143 (27%) microsurgery, and 148 (28%) observation. Multivariable regression analysis revealed that ongoing dizziness was associated with the greatest reduction in PANQOL total score, followed by headache. After adjusting for all examined features, ongoing dizziness and ongoing headache were the only two variables that were associated with both the SF‐36 physical and mental component scores. Patient sex and treatment modality did not significantly influence PANQOL or SF‐36 scores.ConclusionsOngoing dizziness and headache are the strongest predictors of long‐term quality‐of‐life reduction in patients with sporadic VS, while the impact of hearing loss, facial nerve function, and tinnitus are less by comparison. This information may be valuable for patient counseling, refinement of VS quality‐of‐life assessment instruments, and determining high‐yield targets for therapy in efforts to further improve patient outcomes.Level of Evidence4. Laryngoscope, 125:1697–1702, 2015

AbstractWhile fertility is preserved in females with systemic lupus erythematosus (SLE), it is well established that pregnancy in these patients is associated with adverse maternal and fetal outcomes, including pregnancy loss, pre‐eclampsia, preterm delivery and intrauterine growth retardation, as well as neonatal mortality. Mechanisms underlying these adverse outcomes are poorly understood, and better understanding of these would allow development of targeted and personalized treatment strategies. Established risk factors for adverse pregnancy outcomes include active disease within 6 months prior to conception and during pregnancy, active nephritis, maternal hypertension, antiphospholipid antibodies and hypocomplementemia. While intensive monitoring is recommended, the comparative effectiveness of appropriate management strategies is unclear. While current strategies are able to achieve live births in 85–90% of pregnancies, certain aspects such as prevention of preterm birth, treatment of congenital heart block due to neonatal lupus and recurrent pregnancy loss despite best management, remains challenging. Pregnancy is also associated with an increased risk of flare of lupus, particularly in patients with active disease at time of conception or within 6 months prior to conception. Pregnant patients withSLEshould be followed in a high‐risk obstetric clinic, and care should be closely coordinated between the obstetrician and rheumatologist.

BackgroundTranscatheter aortic valve replacement (TAVR) with the balloon‐expandable Sapien transcatheter heart valve improves survival compared to standard therapy in patients with severe aortic stenosis (AS) and is noninferior to surgical aortic valve replacement (AVR) in patients at high operative risk. Nonetheless, a significant proportion of patients may require pre‐emptive or emergent support with cardiopulmonary bypass (CPB) and/or intra‐aortic balloon pump (IABP) during TAVR due to pre‐existing comorbid conditions or as a result of procedural complications. Objectives: We hypothesized that patients who required CPB or IABP would have increased periprocedural complications and reduced long‐term survival. In addition, we sought to determine whether preprocedural variables could predict the need for CPB and IABP. Methods: The study population included 2,525 patients in the PARTNER Trial (Cohort A and B) and the continuing access registry (CAR). Patients that received CPB or IABP were compared to patients that did not receive either, and then further divided into those that received support pre‐TAVR and those that were placed on support emergently. Results: One‐hundred sixty‐three patients (6.5%) were placed on CPB and/or IABP. The use of CPB or IABP was associated with higher 1 year mortality (49.1% vs. 21.6%, P < 0.001). In multivariable analysis, utilization of CPB or IABP was an independent predictor of 30 day (HR 6.95) and 1‐year (HR 2.56) mortality. Although mortality was highest in emergent cases, mortality was also greater in planned CPB and IABP cases compared with non‐CPB/IABP cases (53.3% and 40.3% vs. 21.6%, P < 0.001). Conclusions: These findings indicate that CPB and IABP use in TAVR portends a poor prognosis and its utilization, particularly in the setting of pre‐emptive use, needs reconsideration. © 2015 Wiley Periodicals, Inc.

BackgroundTo evaluate the reliability of MRE using a spin‐echo echo‐planar imaging (SE‐EPI) renal MRE technique in healthy volunteers.MethodsInstitutional review board approved prospective study in which all participants provided written informed consent. Sixteen healthy volunteers comprising seven males and nine females with a median age of 35 years (age range: 23 to 59 years) were included. Coronal 90 Hz and 60 Hz MRE acquisitions were performed twice within a 30‐min interval between examinations. Renal MRE reliability was assessed by (i) test–retest repeatability, and (ii) inter‐rater agreement between two independent readers. The MRE‐measured averaged renal stiffness values were evaluated using: intraclass correlation coefficient (ICC), Bland‐Altman and the within‐subject coefficient of variation (COV).ResultsFor test–retest repeatability, Bland‐Altman showed a mean stiffness difference between examinations of 0.07 kPa (95% limits of agreement: −1.41, 1.54) at 90 Hz and 0.01 kPa (95% limits of agreement: −0.51, 0.53) at 60 Hz. Coefficient of repeatability was 1.47 kPa and 0.52 kPa at 90 Hz and 60 Hz, respectively. The within‐subject COV was 13.6% and 7.7% at 90 Hz and 60 Hz, respectively. ICC values were 0.922 and 0.907 for test–retest repeatability and 0.998 and 0.989 for inter‐rater agreement, respectively (P < 0.001).ConclusionSE‐EPI renal MRE is a reliable technique. J. Magn. Reson. Imaging 2015;42:844–850.

AbstractTissue engineering aims at recapitulating permissive conditions that enable cells to collaborate and form functional tissues. Applications range from human tissue modeling for diagnostic purposes to therapeutic solutions in regenerative medicine and surgery. Across this spectrum, human stem cells are the active ingredient, expandable virtually indefinitely and with the propensity to generate new tissue. Engaging lineage-specific differentiation requires a precise concerto of key spatial and temporal factors, such as soluble molecules and growth factors, but also physical and mechanical stimuli. These stimuli compete to modulate distinct developmental signaling pathways and ultimately affect the differentiation efficiency. The heart is a chemo-mechano-electrical biological system that behaves as both a sensor and an actuator. It can transduce electrical inputs to generate mechanical contraction and electrical wave propagation. Such a complex organ arises from multipart developmental events that interact with one another to self-regulate. Here, we overview the main events of heart development and the role of mechanical forces in modifying the microenvironment of the progenitor cells. We analyze the cascades regulating cardiac gene activation to illustrate how mechanotransduction is already involved in the most popular protocols for stem cell differentiation (SCD) into cardiomyocytes. We then review how forces are transmitted to embryonic stem cells by cell-substrate or cell-cell communications, and how biomaterials can be designed to mimic these interactions and help reproduce key features of the developmental milieu. Putting this back in a clinical perspective, many challenges needs to be overcome before biomaterials-based SCD protocols can be scaled up and marketed. Stem Cells 2015;33:1021–1035